Free-electron lasing at 27 nanometres based on a laser wakefield accelerator.

X-ray free-electron lasers can generate intense and coherent radiation at wavelengths down to the sub-ångström region1-5, and have become indispensable tools for applications in structural biology and chemistry, among other disciplines6. Several X-ray free-electron laser facilities are in operation2-5; however, their requirement for large, high-cost, state-of-the-art radio-frequency accelerators has led to great interest in the development of compact and economical accelerators. Laser wakefield accelerators can sustain accelerating gradients more than three orders of magnitude higher than those of radio-frequency accelerators7-10, and are regarded as an attractive option for driving compact X-ray free-electron lasers11. However, the realization of such devices remains a challenge owing to the relatively poor quality of electron beams that are based on a laser wakefield accelerator. Here we present an experimental demonstration of undulator radiation amplification in the exponential-gain regime by using electron beams based on a laser wakefield accelerator. The amplified undulator radiation, which is typically centred at 27 nanometres and has a maximum photon number of around 1010 per shot, yields a maximum radiation energy of about 150 nanojoules. In the third of three undulators in the device, the maximum gain of the radiation power is approximately 100-fold, confirming a successful operation in the exponential-gain regime. Our results constitute a proof-of-principle demonstration of free-electron lasing using a laser wakefield accelerator, and pave the way towards the development of compact X-ray free-electron lasers based on this technology with broad applications.

A Convolutional Neural Network Model for Distinguishing Hemangioblastomas From Other Cerebellar-and-Brainstem Tumors Using Contrast-Enhanced MRI.

BACKGROUND: Hemangioblastoma (HB) is a highly vascularized tumor most commonly occurring in the posterior cranial fossa, requiring accurate preoperative diagnosis to avoid accidental intraoperative hemorrhage and even death. PURPOSE: To accurately distinguish HBs from other cerebellar-and-brainstem tumors using a convolutional neural network model based on a contrast-enhanced brain MRI dataset. STUDY TYPE: Retrospective. POPULATION: Four hundred five patients (182 = HBs; 223 = other cerebellar-and brainstem tumors): 305 cases for model training, and 100 for evaluation. FIELD STRENGTH/SEQUENCE: 3 T/contrast-enhanced T1-weighted imaging (T1WI + C). ASSESSMENT: A CNN-based 2D classification network was trained by using sliced data along the z-axis. To improve the performance of the network, we introduced demographic information, various data-augmentation methods and an auxiliary task to segment tumor region. Then, this method was compared with the evaluations performed by experienced and intermediate-level neuroradiologists, and the heatmap of deep feature, which indicates the contribution of each pixel to model prediction, was visualized by Grad-CAM for analyzing the misclassified cases. STATISTICAL TESTS: The Pearson chi-square test and an independent t-test were used to test for distribution difference in age and sex. And the independent t-test was exploited to evaluate the performance between experts and our proposed method. P value <0.05 was considered significant. RESULTS: The trained network showed a higher accuracy for identifying HBs (accuracy = 0.902 ± 0.031, F1 = 0.891 ± 0.035, AUC = 0.926 ± 0.040) than experienced (accuracy = 0.887 ± 0.013, F1 = 0.868 ± 0.011, AUC = 0.881 ± 0.008) and intermediate-level (accuracy = 0.827 ± 0.037, F1 = 0.768 ± 0.068, AUC = 0.810 ± 0.047) neuroradiologists. The recall values were 0.910 ± 0.050, 0.659 ± 0.084, and 0.828 ± 0.019 for the trained network, intermediate and experienced neuroradiologists, respectively. Additional ablation experiments verified the utility of the introduced demographic information, data augmentation, and the auxiliary-segmentation task. DATA CONCLUSION: Our proposed method can successfully distinguish HBs from other cerebellar-and-brainstem tumors and showed diagnostic efficiency comparable to that of experienced neuroradiologists. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Real-world cost- effectiveness analysis: Tumor Treating Fields for newly diagnosed glioblastoma in China.

BACKGROUND: Glioblastoma (GBM) stands as the most aggressive and prevalent primary brain malignancy. Tumor Treating Fields (TTFields), an innovative therapy complementing chemotherapy for GBM treatment, which can significantly enhance overall survival, disease progression-free survival, and patient's quality of life. However, there is a dearth of health economics evaluation on TTFields therapy both domestically and internationally. OBJECTIVE: The study aims to assess the cost-effectiveness of TTFields + temozolomide (TMZ) in comparison to TMZ alone for newly diagnosed GBM patients. The intent is to provide robust economic evidence to serve as a foundation for policymaking and decision-making processes in GBM treatment. METHODS: We estimated outcomes for newly diagnosed GBM patients over a lifetime horizon using a partitioned survival model with three states: Progression-Free Survival, Progression Disease, and Death. The survival model was derived from a real-world study in China, with long-term survival data drawn from GBM epidemiology literature. Adverse event rates were sourced from the EF-14 trial data. Cost data, validated by expert consultation, was obtained from public literature and databases. Utility values were extracted from published literature. Using Microsoft Excel, we calculated expected costs and quality-adjusted life years (QALYs) over 15 years from a health system perspective. The willingness-to-pay threshold was set at three times the Chinese per capita Gross Domestic Product (GDP) in 2022, amounting to CN¥242,928 (US$37,655) /QALY. A 5% discount rate was applied to costs and utilities. Results underwent analysis through single factor and probability sensitivity analyses. RESULTS: TTFields + TMZ demonstrated a mean increase in cost by CN¥389,326 (US$57,859) and an increase of 2.46 QALYs compared to TMZ alone. The incremental cost-effectiveness ratio (ICER) was CN¥157,979 (US$23,474) per QALY gained. The model exhibited heightened sensitivity to changes in the discount rate. Probability sensitivity analysis indicates that, under the existing threshold, the probability of TTFields + TMZ being economical is 95.60%. CONCLUSIONS: This cost-effectiveness analysis affirms that incorporating TTFields into TMZ treatment proves to be cost-effective, given a threshold three times the Chinese per capita GDP.

Lethal Electric Field Thresholds for Cerebral Cells With Irreversible Electroporation and H-FIRE Protocols: An In Vitro Three-Dimensional Cell Model Study.

The lethal electric field (LEF) thresholds for three typical cerebral cells, including a malignant glioblastoma (GBM) cell line and two cell lines from the healthy blood-brain barrier (BBB), treated by irreversible electroporation (IRE) or high-frequency irreversible electroporation (H-FIRE) protocols were investigated in an in vitro three-dimensional (3D) cell model. A conventional IRE protocol (90 pulses, 1 Hz, and 100-µs pulse duration) and three novel H-FIRE protocols (1-3-1, 0.5-1-0.5, and 1-1-1) were used to treat the cerebral cells in both 3D single-cell and two-cell models. The electrical conductivity of the 3D cell model under different electric field strengths were characterized with the method of electrochemical impedance spectroscopy (EIS). Based on EIS, a numerical electrothermal model of electroporation was built for the determination of the LEF threshold with different protocols and temperature monitoring. Cell viability was assessed by fluorescence staining 6 h after the treatment. The results showed no thermal lethal effect on cells when these protocols were used. The LEF threshold for GBM cells was significantly lower than that of the healthy BBB cells. These results suggest the possibility of selective ablation of human cerebral GBM by IRE and H-FIRE treatments with no injury or reversible injury to healthy cells, and the potential use of IRE or H-FIRE for transient disruption of the BBB to allow chemotherapy to reach the tumor.

Preparation and Characterization of High Mechanical Strength Chitosan/Oxidized Tannic Acid Composite Film with Schiff Base and Hydrogen Bond Crosslinking.

Chitosan-based composite films with good biodegradability, biocompatibility, and sustainability are extensively employed in the field of food packaging. In this study, novel chitosan/tannic acid (CTA) and chitosan/oxidized tannic acid (COTA) composite films with excellent mechanical and antibacterial properties were prepared using a tape casting method. The results showed that, when 20% tannic acid (TA) was added, the tensile strength of the CTA composite film was 80.7 MPa, which was 89.4% higher than that of the pure chitosan (CS) film. TA was oxidized to oxidized tannic acid (OTA) with laccase, and the phenolic hydroxyl groups were oxidized to an o-quinone structure. With the addition of OTA, a Schiff base reaction between the OTA and CS occurred, and a dual network structure consisting of a chemical bond and hydrogen bond was constructed, which further improved the mechanical properties. The tensile strength of 3% COTA composite film was increased by 97.2% compared to that of pure CS film. Furthermore, these CTA films with significant antibacterial effects against Escherichia coli (E. coli) are likely to find uses in food packaging applications.

Electroporation-Based Therapy for Brain Tumors: A Review.

Electroporation-based therapy (EBT), as a high-voltage-pulse technology has been prevalent with favorable clinical outcomes in the treatment of various solid tumors. This review paper aims to promote the clinical translation of EBT for brain tumors. First, we briefly introduced the mechanism of pore formation in a cell membrane activated by external electric fields using a single cell model. Then, we summarized and discussed the current in vitro and in vivo preclinical studies, in terms of (1) the safety and effectiveness of EBT for brain tumors in animal models, and (2) the blood-brain barrier (BBB) disruption induced by EBT. Two therapeutic effects could be achieved in EBT for brain tumors simultaneously, i.e., the tumor ablation induced by irreversible electroporation (IRE) and transient BBB disruption induced by reversible electroporation (RE). The BBB disruption could potentially improve the uptake of antitumor drugs thereby enhancing brain tumor treatment. The challenges that hinder the application of EBT in the treatment of human brain tumors are discussed in the review paper as well.

The prognosis of glioblastoma: a large, multifactorial study.

OBJECTIVE: Glioblastoma is the most common and fatal primary brain tumor in adults. Even with maximal resection and a series of postoperative adjuvant treatments, the median overall survival (OS) of glioblastoma patients remains approximately 15 months. The Huashan Hospital glioma bank contains more than 2000 glioma tissue samples with long-term follow-up data; almost half of these samples are from glioblastoma patients. Several large glioma databases with long-term follow-up data have reported outcomes of glioblastoma patients from countries other than China. We investigated the prognosis of glioblastoma patients in China and compared the survival outcomes among patients from different databases. METHODS: The data for 967 glioblastoma patients who underwent surgery at Huashan Hospital and had long-term follow-up records were obtained from our glioma registry (diagnosed from 29 March 2010, through 7 June 2017). Patients were eligible for inclusion if they underwent surgical resection for newly diagnosed glioblastomas and had available data of survival and personal information. Data of 778 glioblastoma patients were collected from three separate online databases (448 patients from The Cancer Genome Atlas (TCGA, https://cancergenome.nih.gov), 191 from REpository for Molecular BRAin Neoplasia DaTa (REMBRANDT) database (GSE108476) and 132 from data set GSE16011(Hereafter called as the French database). We compared the prognosis of glioblastoma patients from records among the different databases and the changes in survival outcomes of glioblastoma patients from Huashan Hospital over an 8-year period. RESULTS: The median OS of glioblastoma patients was 16.3 (95% CI: 15.4-17.2) months for Huashan Hospital, 13.8 (95% CI: 12.9-14.9) months for TCGA, 19.3 (95% CI: 17.0-20.0) months for the REMBRANDT database, and 9.1 months for the French database. The median OS of glioblastoma patients from Huashan Hospital improved from 15.6 (2010-2013, 95% CI: 14.4-16.6) months to 18.2 (2014-2017, 95% CI: 15.8-20.6) months over the study period (2010-2017). In addition, the prognosis of glioblastoma patients with total resection was significantly better than that of glioblastoma patients with sub-total resection or biopsy. CONCLUSIONS: Our study confirms that treatment centered around maximal surgical resection brought survival benefits to glioblastoma patients after adjusting to validated prognostic factors. In addition, an improvement in prognosis was observed among glioblastoma patients from Huashan Hospital over the course of our study. We attributed it to the adoption of a new standard of neurosurgical treatment on the basis of neurosurgical multimodal technologies. Even though the prognosis of glioblastoma patients remains poor, gradual progress is being made.

Propagating multi-channel four-wave mixing process in the modulated moving photonic band gap.

Three and four electromagnetically induced transparency windows generate the multi-channel four-wave mixing (FWM) process are observed in a four-level atomic system. The transmission of the probe field and the reflection of the FWM are investigated in the modulated moving photonic band gap structures which are caused by the coupling fields with a relative small detuning offset when scanning detuning frequency of the probe field and the dressing field, respectively. The experimental results show that the more channels spectrum signal of the FWM process can be modulated and the generated multi-channel can be further modulated by adding a dressing field. We have also explained theoretically these experimental results which may have applications in the design of photonic crystal and optical signal amplifiers.

Effect of posterior cervical expansive open-door laminoplasty on cervical sagittal balance.

PURPOSE: Posterior cervical expansive open-door laminoplasty (LAMP) is a mature surgical procedure for the treatment of cervical spondylotic myelopathy (CSM), but there are few studies on the changes in cervical sagittal balance. This study aimed to analyze the imaging and clinical data of patients who underwent LAMP and to explore the effect of this procedure on the cervical sagittal balance. METHODS: This was a retrospective study of the patients who underwent LAMP between 01/2014 and 12/2017. The C0-C2 Cobb angle, sagittal vertical angle (SVA), C2-C7 Cobb angle, and T1-slope were measured. The Japanese Orthopaedic Association (JOA) score, neck disability index (NDI), and visual analog scale (VAS) were used. RESULTS: There were 69 males and 39 females. The mean age was 61.3 ± 5.3 years. The C0-C2 Cobb angle increased from 11.3 ± 5.5° to 26.8 ± 4.8° (P = 0.186). The C2-C7 Cobb angle decreased from 13.9 ± 8.6° to 10.65 ± 10.7° P = 0.016). SVA increased from 21.0 ± 5.8 mm to 25.4 ± 11.5 mm (P = 0.001). The preoperative average JOA score was 11.1 ± 2.2 points, and the postoperative score was 14.0 ± 2.1 points, with an average improvement rate of JOA of 46.5 ± 3.8%. The NDI score decreased from preoperative 15.6 ± 5.4 points to 11.3 ± 7.9 points, and the VAS score was decreased from 4.6 ± 1.8 points to 3.3 ± 1.6 points (all P < 0.05). CONCLUSION: LAMP improved the neurological function and quality of life of patients with CSM. The cervical vertebrae show a tendency of tilting forward, suggesting that overextension of the upper cervical vertebra might be used to maintain the center of gravity of the skull and horizontal vision.

Rapid diagnosis of IDH1-mutated gliomas by 2-HG detection with gas chromatography mass spectrometry.

The metabolic genes encoding isocitrate dehydrogenase (IDH1, 2) are frequently mutated in gliomas. Mutation of IDH defines a distinct subtype of glioma and predicts therapeutic response. IDH mutation has a remarkable neomorphic activity of converting α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), which is now commonly referred to as an oncometabolite and biomarker for gliomas. PCR-sequencing (n = 220), immunohistochemistry staining (IHC, n = 220), and gas chromatography mass spectrometry (GC-MS, n = 87) were applied to identify IDH mutation in gliomas, and the sensitivity and specificity of these strategies were compared. PCR-sequencing and IHC staining are reliable for retrospective assessment of IDH1 mutation in gliomas, but both methods usually take 1-2 days, which hinders their application for rapid diagnosis. GC-MS-based methods can detect 2-HG qualitatively and quantitatively, offering information on the IDH1 mutation status in gliomas with the sensitivity and specificity being 100%. Further optimization of the GC-MS based methodology (so called as the mini-column method) enabled us to determine 2-HG within 40 min in glioma samples without complex or time-consuming preparation. Most importantly, the ratio of 2-HG/glutamic acid was shown to be a reliable parameter for determination of mutation status. The mini-column method enables rapid identification of 2-HG, providing a promising strategy for intraoperative diagnosis of IDH1-mutated gliomas in the future.

Molecular subgroups and B7-H4 expression levels predict responses to dendritic cell vaccines in glioblastoma: an exploratory randomized phase II clinical trial.

Dendritic cell (DC)-based vaccination is a promising approach for active-specific immunotherapy, but is currently of limited efficacy. The safety and effectiveness of a DC vaccine (DCV) loaded with glioblastoma stem cell-like (GSC) antigens was assessed in glioblastoma multiforme (GBM) patients. In this double-blind, placebo-controlled phase II clinical trial, 43 GBM patients were randomized after surgery at a 1:1 ratio to receive either DCV (n = 22) or normal saline placebo (n = 21). Overall survival (OS) and progression-free survival (PFS) were analysed. Participants were stratified into different molecular subgroups based on the mutation (MT) status of isocitrate dehydrogenase (IDH1/2) and telomerase reverse transcriptase (TERT). Plasma cytokine levels, tumor-infiltrating lymphocyte numbers and immune co-inhibitory molecules PD-L1 and B7-H4 were also assessed. Multivariate Cox regression analysis revealed that DCV treatment significantly prolonged OS (p = 0.02) after adjusting for IDH1 and TERT promoter MT and B7-H4 expression, primary vs recurrent GBM. Among IDH1wild type (WT) TERTMT patients, DCV treatment significantly prolonged OS (p < 0.01) and PFS (p = 0.03) and increased plasma levels of cytokines CCL22 and IFN-γ compared with placebo. Patients with low B7-H4 expression showed significantly prolonged OS (p = 0.02) after DCV treatment. Therefore, IDH1WTTERTMT and low B7-H4 expression identified subgroups of GBM patients more responsive to GSC DCV-based specific active-immunotherapy.

Coherent X-ray source generation with off-resonance laser modulation.

The generation of ultrashort coherent radiation in the extreme-ultraviolet (EUV) and soft X-ray regimes is of great significance in a broad range of research. In this paper, a promising scheme for generating coherent harmonic radiation using off-resonance seed laser modulation is discussed. The off-resonance seed laser, whose wavelength differs from the resonant wavelength of the undulator, is first used to modulate the angular distribution of the electron beam (e beam) in the undulator (modulator). After passing through a dispersion section, strong coherent micro-bunching is introduced into the e beam, which contains high-order harmonic components of the seed laser. Theoretical analysis and simulations indicate that this method can be used for the generation of coherent EUV and soft X-ray radiation at sub-gigawatt power in a meter-scale undulator (radiator).

Generation of conditional Acvrl1 knockout mice by CRISPR/Cas9-mediated gene targeting.

OBJECTIVES: This study aimed to generate mutant mice containing the Acvrl1 gene flanked with LoxP sequences to allow conditional deletion of Acvrl1 by the LoxP/Cre system. Such mice may facilitate the development of brain arteriovenous malformation (BAVM) models. METHODS: The CRISPR/Cas9 technique was used to edit Acvrl1. Two single guide RNAs (sgRNAs) with recognition sites on intron 3 and 8 and a donor vector that was homologous with the targeted gene and contained two LoxP sequences were designed and constructed. The in vitro-synthesized sgRNA, Cas9 mRNA and donor vectors were injected into mouse zygotes, which were then transferred into pseudopregnant mice. Neonatal mutant mice were identified by genotyping and sequencing. RESULTS: Two mice with a floxed Acvrl1 allele were generated at a success rate of 8.7%. The target mice, which were healthy and fertile, were obtained through interbreeding. CONCLUSION: CRISPR/Cas9 is a reliable gene-editing tool, and is able to efficiently modify Acvrl1 and create the target mice.

Nucleolin overexpression is associated with an unfavorable outcome for ependymoma: a multifactorial analysis of 176 patients.

Ependymoma typically has a better overall survival rate than most gliomas. Only a few comprehensive clinical studies have been published, but these are mostly from Western countries and use small sample sizes. Histopathological classification is not sufficient to show variable outcomes, and fails to show prognostic markers of the diverse outcomes; hence, it is essential to understand biological mechanisms. In this study, 176 ependymoma samples (World Health Organization grade II and III) were reviewed at Huashan Hospital. Both children and adults were included. We performed multifactorial analyses of clinical prognostic factors and the biomolecular marker expressions of nucleolin, epidermal growth factor receptor (EGFR) and caveolae-associated protein caveolin-1 by immunohistochemistry. We identified the probabilities of progression-free survival and overall survival using univariate and multivariate statistical methods. The participants were diagnosed with ependymomas between 2002 and 2010, including distributions of tumor locations in intracranial and extracranial regions. Nucleolin was overexpressed in 67 % of our samples, demonstrating a subgroup with poor outcome; particularly infratentorial and anaplastic ependymomas. There was no significant correlation between the expression of EGFR and caveolin-1 and clinical outcomes. Clinically, inferior prognosis was observed with regard to age (<18 years), intracranial location, high grade ependymomas, and incomplete resection. We found that nucleolin was an unfavorable prognostic predictor for ependymomas. Moreover, our findings show a subset of aggravating outcomes in high-grade and posterior fossa tumors.

Subgroup characteristics of insular low-grade glioma based on clinical and molecular analysis of 42 cases.

Although the classification of insular glioma has been established based on the anatomical location in order to facilitate personalized surgical resection, the diagnosis based on anatomical and functional characteristics becomes more complex when insular tumors extend into either the frontobasal brain region and/or the temporal lobe, as part of the limbic system. Moreover, prognosis of insular tumor resection is still controversial. Further analysis of subgroup characteristics of insular grade II gliomas based on clinical and molecular analysis is required to reliably determine patients' survival rates. In this retrospective study 20 purely insular grade II gliomas patients and 22 paralimbic grade II gliomas that involved frontal and/or temporal lobes were compared with regard to epidemiological and clinical characteristics. The molecular profiles including Isocitrate dehydrogenase 1 (IDH1), telomerase reverse transcriptase (TERT) promoter, and P53 mutations, 1p19q co-deletion were analyzed, and microRNA profiles were assessed by microarray and bioinformatics analysis. Purely insular grade II gliomas displayed a high frequency of IDH1 mutations with favorable outcome. IDH1 mutated paralimbic glioma shared many parameters with the purely insular glioma in respect to growth patterns, survival, and microRNA profile, but differed significantly from the IDH1 wild type paralimbic gliomas. Our findings suggest that IDH1 mutations can define subpopulations of insular gliomas with distinct disease entities regardless of tumor extension patterns. These findings could be useful to develop a customized treatment strategy for insular glioma patients.

Establishment and maintenance of a standardized glioma tissue bank: Huashan experience.

Cerebral glioma is the most common brain tumor as well as one of the top ten malignant tumors in human beings. In spite of the great progress on chemotherapy and radiotherapy as well as the surgery strategies during the past decades, the mortality and morbidity are still high. One of the major challenges is to explore the pathogenesis and invasion of glioma at various "omics" levels (such as proteomics or genomics) and the clinical implications of biomarkers for diagnosis, prognosis or treatment of glioma patients. Establishment of a standardized tissue bank with high quality biospecimens annotated with clinical information is pivotal to the solution of these questions as well as the drug development process and translational research on glioma. Therefore, based on previous experience of tissue banks, standardized protocols for sample collection and storage were developed. We also developed two systems for glioma patient and sample management, a local database for medical records and a local image database for medical images. For future set-up of a regional biobank network in Shanghai, we also founded a centralized database for medical records. Hence we established a standardized glioma tissue bank with sufficient clinical data and medical images in Huashan Hospital. By September, 2013, tissues samples from 1,326 cases were collected. Histological diagnosis revealed that 73 % were astrocytic tumors, 17 % were oligodendroglial tumors, 2 % were oligoastrocytic tumors, 4 % were ependymal tumors and 4 % were other central nervous system neoplasms.

Heterogeneity effects of environmental regulation policy synergy on ecological resilience: considering the moderating role of industrial structure.

Given the great importance attached to ecological civilization and green development, exploring the heterogeneous effects of environmental regulation policy synergy on ecological resilience holds significance for improving environmental protection and the design of environmental policies. Based on the policy synergy perspective, this paper uses 30 provinces (municipalities and autonomous) in China as the research sample. Bayesian quantile regression is employed to explore the heterogeneous effects of environmental regulation policy synergy on ecological resilience from 2007 to 2021, and the moderating effect of the industrial structure is examined. The results indicate the following: (1) there is significant heterogeneity and variability in the effect of environmental regulation policy synergy on ecological resilience. Specifically, the effects of policy mixes 12, 13, and 23 on ecological resilience shows a U-shaped trend, while the impact of policy mix 123 on ecological resilience shows a positive effect. (2) There are significant differences in the effects of environmental regulation policy synergy under different quantiles of ecological resilience. Taking policy mix 12 as an example, we find that the effect of policy synergy on ecological resilience tends to decrease and then increase at a lower quantile. Additionally, the effect of policy synergy on ecological resilience tends to be positive at a higher quantile. (3) There are significant differences in the moderating effects of the industrial structure. Policy mix 12 can effectively enhance ecological resilience through industrial structure upgrading, while the moderating effects of alternative policy combinations are deemed insufficient. Finally, relevant policy recommendations are proposed to effectively improve ecological resilience.

Single-Cell Transcriptomics Reveals the Heterogeneity of the Immune Landscape of IDH-Wild-Type High-Grade Gliomas.

Isocitrate dehydrogenase (IDH)-wild-type (WT) high-grade gliomas, especially glioblastomas, are highly aggressive and have an immunosuppressive tumor microenvironment. Although tumor-infiltrating immune cells are known to play a critical role in glioma genesis, their heterogeneity and intercellular interactions remain poorly understood. In this study, we constructed a single-cell transcriptome landscape of immune cells from tumor tissue and matching peripheral blood mononuclear cells (PBMC) from IDH-WT high-grade glioma patients. Our analysis identified two subsets of tumor-associated macrophages (TAM) in tumors with the highest protumorigenesis signatures, highlighting their potential role in glioma progression. We also investigated the T-cell trajectory and identified the aryl hydrocarbon receptor (AHR) as a regulator of T-cell dysfunction, providing a potential target for glioma immunotherapy. We further demonstrated that knockout of AHR decreased chimeric antigen receptor (CAR) T-cell exhaustion and improved CAR T-cell antitumor efficacy both in vitro and in vivo. Finally, we explored intercellular communication mediated by ligand-receptor interactions within the tumor microenvironment and PBMCs and revealed the unique cellular interactions present in the tumor microenvironment. Taken together, our study provides a comprehensive immune landscape of IDH-WT high-grade gliomas and offers potential drug targets for glioma immunotherapy.

Comprehensive molecular characterization of long-term glioblastoma survivors.

Fewer than 5 % glioblastoma (GBM) patients survive over five years and are termed long-term survivors (LTS), yet their molecular background is unclear. The present cohort included 72 isocitrate dehydrogenase (IDH)-wildtype GBM patients, consisting of 35 LTS and 37 short-term survivors (STS), and we employed whole exome sequencing, RNA-seq and DNA methylation array to delineate this largest LTS cohort to date. Although LTS and STS demonstrated analogous clinical characters and classical GBM biomarkers, CASC5 (P = 0.002) and SPEN (P = 0.013) mutations were enriched in LTS, whereas gene-to-gene fusions were concentrated in STS (P = 0.007). Importantly, LTS exhibited higher tumor mutation burden (P < 0.001) and copy number (CN) increase (P = 0.013), but lower mutant-allele tumor heterogeneity score (P < 0.001) and CN decrease (P = 0.026). Additionally, LTS demonstrated hypermethylated genome (P < 0.001) relative to STS. Differentially expressed and methylated genes both enriched in olfactory transduction. Further, analysis of the tumor microenvironment revealed higher infiltration of M1 macrophages (P = 0.043), B cells (P = 0.016), class-switched memory B cells (P = 0.002), central memory CD4+ T cells (P = 0.031) and CD4+ Th1 cells (P = 0.005) in LTS. We also separately analyzed a subset of patients who were methylation class-defined GBM, contributing 70.8 % of the entire cohort, and obtained similar results relative to prior analyses. Finally, we demonstrated that LTS and STS could be distinguished using a subset of molecular features. Taken together, the present study delineated unique molecular attributes of LTS GBM.

Single Nucleus Total RNA Sequencing of Formalin-Fixed Paraffin-Embedded Gliomas.

Gliomas, the predominant form of brain cancer, comprise diverse malignant subtypes with limited curative therapies available. The insufficient understanding of their molecular diversity and evolutionary processes hinders the advancement of new treatments. Technical complexities associated with formalin-fixed paraffin-embedded (FFPE) clinical samples hinder molecular-level analyses of gliomas. Current single-cell RNA sequencing (scRNA-seq) platforms are inadequate for large-scale clinical applications. In this study, automated snRandom-seq is developed, a high-throughput single-nucleus total RNA sequencing platform optimized for archival FFPE samples. This platform integrates automated single-nucleus isolation and droplet barcoding systems with the random primer-based scRNA-seq chemistry, accommodating a broad spectrum of sample types. The automated snRandom-seq is applied to analyze 116 492 single nuclei from 17 FFPE samples of various glioma subtypes, including rare clinical samples and matched primary-recurrent glioblastomas (GBMs). The study provides comprehensive insights into the molecular characteristics of gliomas at the single-cell level. Abundant non-coding RNAs (ncRNAs) with distinct expression profiles across different glioma clusters and uncovered promising recurrence-related targets and pathways in primary-recurrent GBMs are identified. These findings establish automated snRandom-seq as a robust tool for scRNA-seq of FFPE samples, enabling exploration of molecular diversities and tumor evolution. This platform holds significant implications for large-scale integrative and retrospective clinical research.